Leukotriene (LT)E4, the terminal product of cysteinyl leukotriene (cys-LT) generation, is a weak agonist of the classical cysteinyl leukotriene receptors (CysLTRs), but a potent inducer of bronchial eosinophilia and airway hyperresponsiveness in humans. LTE4 abounds in the airways of asthmatics, and is especially abundant in the lungs and nasal tissues of patients with aspirin-exacerbated respiratory disease (AERD). ADP, an abundant extracellular nucleotide, is the natural ligand for P2Y12 and P2Y1 receptors. In the current funding period, we determined that LTE4 markedly potentiates airway inflammation in sensitized mice through a pathway that is completely independent of classical CysLTRs, and requires both P2Y12 receptors and platelets. Surprisingly, however, LTE4 exhibits no direct binding at P2Y12 receptors. We have found that ADP is a molecular mimic of LTE4 in vivo, with potential function as an amplifier of pulmonary inflammation. The continuation of this proposal focuses on the mechanism(s) and cellular targets that are responsible for the effects of LTE4 in pulmonary inflammation, and the role of P2Y12 receptors in this process. The findings are expected to have immediate implications for asthma pathophysiology and treatment, especially in AERD, in which there is a substantial component of the disease that is driven by cys-LTs. This proposal is based on the central hypotheses that 1. P2Y12 receptors mediate a convergent pathway by which adenosine diphosphate (ADP) and leukotriene (LT)E4, respectively, facilitate the migration of effector cells to the allergen-challenged lung through platelet-dependent mechanisms, and 2. P2Y12 receptors interact with at least one additional GPCR to create a functional receptor for LTE4, and also interact with P2Y1 receptors to form a receptor complex for ADP. These complexes mediate the respective LTE4-dependent and LTE4-indepedent features of P2Y12 receptor contributions to pulmonary inflammation. PUBLIC HEALTH RELEVANCE: Leukotriene E4 (LTE4) is a chemical produced by the body's immune system that causes inflammation. High levels of LTE4 are present in the lungs of patients with asthma, a common serious disease. This proposal seeks to identify the cells and molecules that enable LTE4 to cause inflammation. The goal is to find more effective treatments for asthma and other allergic diseases.